ABSTRACT Aging is the undisputed main risk factor for onset of Alzheimer disease (AD) and many other dementias, yet is underinvestigated, because of perceived inability to modify aging. Moreover, aging research is time- consuming, laborious and expensive. However, we and others have recently made significant advances in identifying DNA damage as (the) main cause of aging and the ability to accelerate, target and delay aging in progeroid repair-deficient mouse models for rare human progeroid repair syndromes. These mice show prominent progressive, bona-fide neurodegeneration exhibiting very strong similarities to human dementias regarding histopathology, physiology, behavior (loss of cognition, memory, motor performance), neuronal loss and spontaneous protein aggregation. We also discovered development of transcriptional stress in aged liver in prematurely and normal aging mice, most likely due to persistent DNA damage interfering with gene expression. This novel phenomenon in aging leading to imbalanced and reduced transcriptional output could provide a logical explanation for aging-associated protein aggregation as common denominator in all proteinopathies including AD. Therefore, we will critically test the hypothesis that human AD suffers from enhanced transcription stress by analyzing brains of normal and accelerated aging mice and in available transcriptomics datasets of AD patients to better understand the contribution of aging as the main risk factor for the onset of neurodegeneration, most notably protein aggregation. This knowledge is a prerequisite for developing rational-based anti-aging interventions, which prevent or delay progression of AD and other dementias, addressing a tremendous unmet medical need.